Tyramine as a Prolific Coformer in Crystal Engineering: Insights from Classical Crystal Structure Analysis and Electron Density Studies

Prolific coformers are compounds that readily form multicomponent crystals with diverse partners, playing a crucial role in crystal engineering by enabling the creation of new solids with enhanced physicochemical properties. In this study, we investigated tyramine as a potentially attractive cocrystallization component, given its reported ability in the Cambridge Structural Database (CSD) to interact with over 60 diverse building blocks. We conducted classical crystal structure and charge density analyses, along with Hirshfeld surface studies, on three distinct tyramine organic salts with L-pyroglutamic acid, D-mandelic acid, and p-aminohippuric acid. This work aimed to determine whether and why tyramine can be considered a prolific coformer. Tyramine cations were evaluated in terms of similarities and differences in intermolecular interactions across these salts. Additionally, we examined the conformation of the aliphatic chain and ΔpK_a values for all tyramine salts in the CSD to identify the most significant factors influencing cocrystallization with tyramine. Our findings suggest that proton transfer is a crucial factor in the formation of stable multicomponent materials with tyramine. Furthermore, the selection of coformers for cocrystallization with tyramine should prioritize repeatable synthons, particularly those containing carboxylic groups.

Tyramine’s prolific cocrystallization behavior, evaluated through crystal structure, charge density, Hirshfeld surface, and ΔpK_a analysis, highlights its potential as a versatile coformer for multicomponent crystals.